University of Ottawa Institute of Mental Health Research, Ottawa, Ont.

Abstract

Background: The only antidepressant drugs that are effective in the treatment of obsessive–compulsive disorder (OCD) are those that effectively block the reuptake of serotonin (5-hydroxytryptamine; 5-HT). In humans, positron emission tomography studies have implicated the orbitofrontal cortex (OFC) in the mediation of OCD symptoms. In animals, administration of selective serotonin reuptake inhibitors (SSRIs) for 8 weeks (but not 3 weeks) led to increased release of 5-HT in the OFC, because of desensitization of the terminal 5-HT autoreceptors. However, the increase in synaptic levels of 5-HT in the OFC after long-term administration of SSRIs might be cancelled out by desensitization of postsynaptic 5-HT receptors. This study was undertaken to investigate if these OFC receptors adapt under such conditions.

Methods: In vivo electrophysiologic techniques were used in this animal study. Male Sprague–Dawley rats received the SSRI paroxetine or vehicle control, delivered by implanted osmotic minipumps, for 3 or 8 weeks. With the rats under anesthesia, neuronal responsiveness to the microiontophoretic application of various drugs was assessed by determining the number of spikes suppressed per nanoampere of ejection current.

Results: After administration of paroxetine for either 3 weeks or 8 weeks, there was no modification in the inhibitory effect of 5-HT, the preferential 5-HT2A receptor agonist (+)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane hydrochloride (DOI) or the preferential 5-HT2C receptor agonist 3-chlorophenyl piperazine dihydrochloride (mCPP). In contrast, the inhibitory effect of the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propilamino)-tetralin (8-OH-DPAT) was attenuated in the OFC after both 3 and 8 weeks of paroxetine administration.

Conclusion: These results indicate a desensitization of postsynaptic 5-HT1A receptors in the OFC but a lack of compensatory adaptation of the 5-HT receptor(s) mediating the main effect of 5-HT in this brain region. These observations imply that the activation of normosensitive postsynaptic 5-HT2-like receptors may mediate the effect of enhanced 5-HT release in the OFC.

Acknowledgements: This work was supported by a Canadian Institutes for Health Research grant and by salary support from the University of Ottawa Institute of Mental Health Research to both authors, as well as a Research Chair in Psychopharmacology from the Canadian government to Dr. Blier.

Competing interests: None declared.

Contributors: Drs. El Mansari and Blier conceived and designed the study, collected and interpreted the data, drafted and revised the article, and gave final approval for it to be published.